What's Hot in PD? Pimavanserin and the Hope for a Better Drug for Hallucinations and Psychosis in Parkinson’s Disease

When we recently examined the topics that were most searched for on our website, we were not surprised to discover that treatment of psychosis and hallucinations in Parkinson’s disease topped the list. There has been a critical unmet need for development of better drugs to address hallucinations and psychosis in the setting of Parkinson's disease. We have learned over many years of experience that typical high potency neuroleptic antipsychotic drugs (such as Haldol, Olanzapine) may improve hallucinations, but do so at the cost of worsening Parkinson’s disease motor symptoms (rigidity, slowness, and walking). We have therefore changed our strategy to address hallucinations in Parkinson’s disease by using agents that will not worsen the motor symptoms (stiffness, slowness, walking). We routinely choose quetiapine (seroquel) or clozapine (clozaril) instead of the classical dopamine blocking drugs. There are however, shortcomings with these two drugs. Quetiapine has not been shown effective in several randomized Parkinson’s clinical trials, however many Parkinson experts believe it is moderately helpful, particularly in mild hallucinations. Clozapine has been shown to be highly efficacious, but it requires weekly blood monitoring to check for a potentially life-threatening side effect called agranulocytosis (the drug attacks the bone marrow). The inconvenience and discomfort of blood draws have limited the penetration of this therapy. Pimavanserin is a new drug that works on the serotonin receptor, without blocking the dopamine receptor.

Here are some tips about what you need to know about Pimavanserin for treatment of Parkinson's disease related psychosis.

Though classically we think about the dopamine receptor in Parkinson's disease as underpinning psychosis symptoms, serotonin has also been implicated.

Lysergic acid diethylamide and phencyclidine (PCP) seem to stimulate 5HT2A serotonin type of receptors. Stimulation of these receptors may lead to hallucinations.

Most available antipsychotic drugs block the 5HT2A receptor and the D2 dopamine receptor.

It is possible that the 5HT2A blocking mechanisms of newer antipsychotics may underpin their benefit and may do so with low side effect portfolio.

Pimavanserin is a 5HT2A inverse agonist (binds to the same receptor as an agonist; an agonist would stimulate the receptor, but an inverse agonist would do the opposite and reduce stimulation below basal levels for the serotonin brain receptor)

Pimavanserin is not thought to have motor side effects (i.e. tardivedyskinesia, parkinsonism)

The emerging safety profile has shown it is superior to other available antipsychotics

There is one Phase III trial that has shown benefit

The company is planning to pursue FDA approval for Parkinson's disease (it has been previously used in Schizophrenia)

It is possible that Pimavanserin will be another great alternative for some patients with Parkinson's disease, especially since it does not worsen motor symptoms, however more data will be needed. One wonders if in severe cases of psychosis, Pimavanserin could be added to seroquel or clozaril to improve treatment of difficult to control hallucinations

Patient should keep in mind that there are a few general rules that most experts will employ when treating psychosis. First, practitioners will discontinue or reduce dosages of many hallucination and psychosis triggering medications (amantadine, MAO-B inhibitors, anticholinergics, entacapone, and dopamine agonists). Sometimes, patients can be maintained on sinemet only (carbidopa/levodopa) regimens, or by reducing sinemet dose and increasing the frequency of dose administrations. When these strategies don’t work, many PD experts turn to quetipine, clozapine, and maybe in the near future Pimavanserin.


You can find out more about our National Medical Director, Dr. Michael S. Okun, by also visiting the Center of Excellence, University of Florida Health Center for Movement Disorders and Neurorestoration. Dr. Okun is also the author of the Amazon #1 Parkinson's Best Seller 10 Secrets to a Happier Life and 10 Breakthrough Therapies for Parkinson's Disease.

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