Pimavanserin May Be Optimal for Treating Parkinson’s Disease Psychosis

Parkinson’s disease (PD) is traditionally regarded as a movement disorder, but it is actually a neuropsychiatric disorder with multiple psychiatric symptoms such as hallucinations, delusions, depression, and anxiety. Parkinson’s disease psychosis (PDP) is arguably the most serious and disruptive to both the patients and caregivers, many of whom are family members. PDP occurs in over 50 percent of PD patients and often leads to hospitalization and/or nursing home placement (1).

Typically, PDP begins with a visual hallucination of insects, animals, or people. While the patient typically recognizes these hallucinations at first, as they become more frequent and vivid, the patient loses insight and believes they are real. Other types hallucinations, including auditory, olfactory, or gustatory, sometimes occur as well, but not as frequently as visual hallucinations.

Delusions start emerging as PD progresses. The most common fixed, false beliefs involve an accusation of marital infidelity, which can be very hurtful to the spouse who is often the caregiver. Such delusions can elicit a variety of reactions from patients (for instance, we’ve treated patients who have accused long-time spouses of planning to kill them) and are a major reason for admission to a gero-psychiatry hospital unit or to a nursing home, where the risk of mortality is quite high.

Unfortunately, the patient and family/caregivers often do not inform the treating physician about the hallucinations or delusions during the routine visits for Parkinson’s symptoms. This may be due to embarrassment or a belief that those psychotic symptoms have nothing to do with PD. Thus, physicians must inquire about such psychotic symptoms at each visit so they can be treated early and before such symptoms intensify.

Diagnosing PDP is quite straightforward. The patient must have a preexisting diagnosis of PD and have experienced hallucinations or delusions for at least one month, which may also include a false sense of presence (a distinct feeling that someone is around or passed by although nobody is there). Exclusion criteria include the absence of another psychotic illness, such as delirium, schizophrenia, psychotic depression, or Alzheimer’s disease psychosis.

While clinicians once prescribed first-generation neuroleptics to treat PDP, these strong dopamine antagonists can cause severe worsening of motor symptoms. More recently, second-generation antipsychotics (SGAs) have emerged as an option for patients with PDP. By virtue of their strong 5HT2A binding, SGAs cause less iatrogenic parkinsonism and other extrapyramidal side effects than first-generation antipsychotics.

Until last spring, the U.S. Food and Drug Administration (FDA) had yet to approve an antipsychotic for the treatment of PDP. Neurologists and psychiatrists mostly prescribed patients with PDP quetiapine or clozapine off-label in small doses. While these medications can ameliorate symptoms of psychosis, they can also cause serious side effects such as worsening of motor symptoms, sedation, constipation, orthostasis, and falls.

In April 2016, the FDA approved Acadia’s Nuplazid (pimavanserin) tablets for the treatment of hallucinations and delusions associated with psychosis in people with PD. This was a major triumph for psychopharmacology research because unlike all antipsychotic drugs used over the past 60 years, pimavanserin does not block dopamine D2 receptors and therefore avoids worsening PD motor symptoms while controlling hallucinations and delusions.

Pimavanserin is a selective serotonin 5HT-2A inverse agonist and antagonist, which leads to very strong antagonism of the 5HT-2A receptors. (Interestingly, recent research has demonstrated increased serotonin 5HT-2A activity in PD, especially in the ventral visual cortex [3,4]).

The FDA’s decision to approve pimavanserin was based on the results of a trial in which adults with PDP were randomly assigned to take 40 mg of pimavanserin or placebo daily for six weeks. Patients taking pimavanserin experienced fewer and less severe hallucinations and delusions without worsening the primary motor symptoms of PD. (5)

The side effects of pimavanserin included the following: nausea (7 percent versus 4 percent for placebo), peripheral edema (7 percent versus 2 percent), confusional state (8 percent versus 3 percent), hallucinations (5 percent versus 3 percent), constipation (4 percent versus 3 percent), gait disturbance (2 percent versus <1 percent), urinary tract infection (1 percent versus <1 percent), and fatigue (4 percent versus 0 percent).

Pimavanserin is available in 17 mg tablets. The standard dose is 34 mg/day at any time, with or without food. No titration is required regardless of the patient’s age. The only time when one tablet should be used is when a patient is also receiving a strong CYP3A4 inhibitor, to decrease the likelihood of side effects. In contrast, three tablets are appropriate if the patient is receiving a strong CYP3A4 inducer, to avoid loss of efficacy.

As the only FDA-approved antipsychotic for PDP, pimavanserin should be the first choice for patients newly diagnosed with PDP. However, for the PDP patients who are already being treated with an off-label antipsychotic, such as quetiapine, a switch to pimavanserin should be done gradually in a cross-taper approach. This will avoid withdrawal symptoms, such as insomnia due to the abrupt discontinuation of a sedating medication like quetiapine.

Additionally, because pimavanerin’s onset of therapeutic action is two to four weeks, it is preferable to add pimavanserin to an existing dose of quetiapine for approximately four to six weeks before the quetiapine dose is gradually reduced over another four to six weeks. If the PDP symptoms do not improve with pimavanserin after 10 to 12 weeks, then augmentation with a low dose of an atypical antipsychotic is justified.

Finally, the clinical trial of pimavanserin showed a spectrum of responses, but 65 percent of patients in the study experienced a reduction in PDP and 13.7 percent of patients had complete resolution of symptoms at six weeks compared with 1.1 percent of patients taking placebo. The variation in response is to be expected because PD is now recognized as a heterogeneous syndrome with close to a dozen etiologies. Thus, a variable response is to be expected among patients with PDP.

In conclusion, pimavanserin is a welcome paradigm shift in antipsychotic pharmacotherapy because it is the first agent approved to treat psychosis without blocking dopamine D2 receptors. Trials have been initiated to test its efficacy and safety for other psychotic disorders such as schizophrenia and Alzheimer’s disease psychosis. With the development of pimavanserin, PDP patients can benefit from a medication that does not worsen motor movements, unlike previous treatment options. ■