AAN 2025 | Understanding Parkinson’s disease psychosis: pathophysiology and treatment strategies

In Parkinson’s disease, we’ve focused for so long on dopamine and dopaminergic degeneration and the loss of striatal dopamine as underlying motor symptoms. And we’ve also looked at a number of non-motor symptoms and looked at perhaps that they’re caused by dopamine replenishment, but giving too much dopamine in certain parts of the nervous system. For instance, orthostatic hypotension, occurs when we give or increase dopaminergic therapies, has been thought about to be drug-induced. But now we learn that it’s really a symptom of autonomic failure and noradrenergic deficiency and suboptimal release of norepinephrine upon standing. And this leads to orthostatic hypotension, which can then be accentuated by dopaminergic therapies, other therapies, antihypertensives, relative dehydration, heat and food, etc. A similar situation occurs with other non-motor symptoms, for instance, with Parkinson’s disease psychosis. It wasn’t so long ago that we thought about Parkinson’s disease psychosis as a drug-induced psychosis from dopaminergic therapies. But as studies continue to accumulate, we identified that the major cause of Parkinson’s psychosis in most people with Parkinson’s disease is not due to dopaminergic therapy, but rather due to a serotonergic dysfunction. Loss of serotonin neurons in the raphae nuclei in Parkinson’s disease occurs very early in the disease, often predating dopaminergic degeneration. And this loss of serotonin leads to an upregulation of serotonin 2A receptors in corticoglutamatergic neurons. And this leads to an overactivity of these neurons because the serotonin 2A receptor has intrinsic activity and is always active. So when they’re upregulated, you have increased activity. In the visual cortex, it may lead to visual hallucinations, but it also leads to descending drive of the mesolimbic dopaminergic pathway. And this can give rise to delusions and other hallucinations as well. Atypical antipsychotics are atypical because in addition to blocking postsynaptic dopamine D2 receptors, like first-generation neuroleptics do, they also block serotonin 2A receptors. So we have been aware of this, but almost all currently available antipsychotics block dopamine D2 receptors and worsen motor Parkinson’s disease, really giving us a therapeutic bind in that if we try to treat Parkinson’s disease psychosis by reducing dopamine therapies, patients have worse motor function. If we try adding an antipsychotic to block serotonin 2A, it also blocks dopamine receptors, worsening motor function. So we really needed to identify a way of treating Parkinson’s psychosis without worsening motor function. Clozapine, which was one of the early atypical antipsychotics, seemed not to have high enough occupancy at the D2 receptor and did not worsen motor function in two four-week trials conducted years ago, now one in the U.S. and one in France, that improved Parkinson’s psychosis without worsening motor function. Quetiapine has been studied because it doesn’t seem to worsen motor function in most patients, but efficacy could not be demonstrated in a number of smaller studies. Pimavanserin was a novel medication that was developed by a company called Acadia that only was selective for the serotonin 2A receptor and had no D2 affinity or occupancy and no other off-target receptors such as adrenergic which could lead to orthostatic hypotension or histamine receptors that could lead to somnolence. So it was an interesting compound and when we studied this in Phase II and Phase III trials, we’re able to demonstrate efficacy in improving Parkinson’s psychosis and also without worsening motor function. So there’s only two antipsychotics that have been proven to improve Parkinson’s psychosis symptoms without worsening motor symptoms in people with Parkinson’s disease, clozapine and pimavanserin. Quetiapine can also be used because it doesn’t seem to worsen motor function, but we have to beware off target side effects like orthostatic hypotension and somnolence. And some recent real-world evidence has suggested that when patients are on pimavanserin compared to using other antipsychotics in these analysis, about 80% or more of the patients were on quetiapine. Pimavanserin exhibited over this period of time, looking at these large real-world Medicare database retrospective analyses, reduced mortality compared to other atypical antipsychotics in Parkinson’s disease. And other analyses look like reduced falls and hospitalizations as well. So it began to dawn on us that we needed to really think about, is this time now to offer some guidance, some guidance on how to approach patients with Parkinson’s disease psychosis in the clinic? So we thought it would be important to gather some experts in Parkinson’s psychosis, both psychiatrists with an interest in Parkinson’s psychosis, as well as some movement disorder specialist, Parkinson’s neurologists who have interest in Parkinson’s psychosis, to sort of offer some guidance of how to approach these patients, first-line therapy options and such. And we recently were able to have this guidance published in the Expert Opinion of Pharmacotherapy. We included other Parkinson’s neurologists like Rajesh Power and Daniel Kremins, psychiatrists who are well-known in the field, like Henry Ness Roller and Gus Alvar and Stephen Stahl, and we’re able to have these guidelines now out there, have these guidelines out there for discussion and for debate, and also to offer a consensus and some guidance, perhaps, for people who see these patients in clinic and really wanted to know, what should I use first? How should I switch? How should I address problems that may remain in patients living with Parkinson’s disease to really get out of this therapeutic bind, to treat Parkinson’s psychosis without worsening motor function, to keep patients improved with both motor and non-motor symptoms, which I think is really an emerging theme in some of our novel therapies. And I think it’ll be helpful because pimavanserin is first-line therapy because of its demonstrated efficacy, safety, and tolerability. Clozapine can also be used, but is off-label in the U.S. and requires a regular blood monitoring weekly for six months, biweekly for another six months, and then monthly thereafter because of a risk of agranulocytosis that can occur in 1% of patients treated. So it’s often not regulated, not used as first-line therapy. Quetiapine, because of its propensities of causing orthostatic hypotension and sedation as off-target side effects and its lack of demonstrated efficacy, is felt to be a second-line option and all other antipsychotics should not be used in people with Parkinson’s disease because of their regularity of worsening motor symptoms and this is reflected in evidence-based reviews with the Movement Disorder Society the bears criteria American Geriatric Society. So I think there’s this good consensus on that so hopefully this recent publication will allow some some discussion and some dialogue but also some guidance for people who are seeing patients regularly in the clinic and have to treat the Parkinson’s psychosis.

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