Dementia is a constellation of progressive cognitive problems, such as memory loss and disorientation, which occurs in Alzheimer’s disease, Parkinson’s disease, and other diseases that reduce brain function.

But dementia affects more than cognition.

Hallucinations occur in up to 50% of the 50 million cases of dementia worldwide, and delusions occur in up to 75% of cases, together collectively referred to as "dementia-related psychosis." Although not as well known as the hallmark cognitive decline, dementia-related psychosis takes a heavy toll on people who experience psychosis symptoms and those who care for them.

There are no approved medications for dementia-related psychosis. Off-label use of antipsychotic medications, developed to treat the psychosis symptoms associated with schizophrenia, is common in clinical practice. But, the use of traditional antipsychotics for dementia-related psychosis  is problematic because these drugs are often ineffective and come with a litany of dangerous side-effects, including excessive sedation, cardiovascular problems, and increased cognitive decline. In fact, the FDA issued a black-box warning against treating dementia-related psychosis with some traditional antipsychotic medications due to safety concerns. With limited treatment options for dementia-related psychosis and the number of cases of dementia increasing by 10 million per year, developing safe and effective medications for dementia-related psychosis is a major clinical need.

Now, as the result of work conducted by researchers at the University of Exeter and Acadia Pharmaceuticals, scientists may have identified a drug that can prevent dementia-related psychosis for a long period of time with few side-effects. The drug, called pimavanserin, affects the brain differently than the antipsychotics developed for schizophrenia by specifically and strongly blocking a type of serotonin receptor in the brain called 5-HT2A.

The likely explanation for why traditional antipsychotic medications don't work for dementia-related psychosis is that they were never developed to treat episodes of psychosis in elderly people with dementia; they were developed for young people with schizophrenia. Dementia and schizophrenia are different diseases with different neurological causes, so there is no guarantee that their symptoms will respond to the same medications. In addition, levels of neurotransmitters in the brain change as humans age, which could influence the effects of psychoactive drugs.

In preclinical studies, pimavanserin reduced psychotic behavior in rodents and clinical testing sponsored by Acadia Pharmaceuticals showed that pimavanserin improved psychosis symptoms in people with Parkinson's disease and Alzheimer's disease. In 2016, pimvanserin became the first drug to receive FDA approval as a treatment for Parkinson's-related psychosis and was taken to market by Acadia Pharmaceuticals under the brand name NUPLAZID.

With positive clinical data for psychosis symptoms in Alzheimer's disease and FDA approval for psychosis symptom's in Parkinson's disease, Acadia Pharmaceuticals initiated a clinical trial of pimavanserin for additional subtypes of dementia-related psychosis in 2017. A total of 392 people with Alzheimer's disease, Parkinson's disease, Lewy body, frontotemporal, or vascular dementia participated in the study and the results were published in the New England Journal of Medicine in July of 2021.

For the first 12-weeks of the study, all the participants received pimavanserin open-label. After week 12, participants who met a certain threshold of symptomatic improvement were randomly assigned to receive either pimavanserin or a placebo for 26 weeks to determine if the drug could prevent relapse of psychosis symptoms. The drug was found to be so effective at preventing relapse of psychosis symptoms, however, that the trial was stopped before its intended endpoint at 26 weeks because it would have been unethical to continue giving the control group the placebo. When the trial was stopped, relapse occurred in 28.3% of the placebo group compared to just 12.6% in the pimavanserin group, with minimal side-effects.

The results of the study are encouraging, but it had several limitations due to the participants it included. One of the more glaring issues is that over 98% of study participants included in the trial after week 12 were white. This, despite “white” individuals being at a lower risk of dementia compared to “African American” and “Hispanic” individuals according to the Centers for Disease Control and Prevention. In addition, 15% of the participants had dementia-related psychosis due to Parkinson’s disease, a condition for which pimavanserin has already been approved for as a treatment. Therefore, as the researchers admit, the data generated by these participants “may have skewed the results in favor of pimavanserin.”

But the study's most significant limitation, at least as far as FDA approval is concerned, is that the trial had insufficient statistical power to detect whether pimavanserin improved psychosis symptoms in individual subtypes of dementia. In April of 2021, the FDA notified Acadia Pharmaceuticals that after reviewing the existing clinical trial data the agency would not approve pimavanserin as a treatment for dementia-related psychosis, citing an insufficient number of participants with less-common dementia subtypes and a lack of statistical significance in some subgroups of dementia.

For the team at Acadia Pharmaceuticals, the FDA's decision came as a surprise. Generating and analyzing clinical data from study populations that include a mix of dementias without necessarily separating them has become an accepted practice when treating the psychosis symptoms associated with dementia.

Although next steps are not certain, Acadia CEO Stephen Davis outlined three possible outcomes. First, as is the company's position, they could proceed by performing additional statistical analyses of the existing data without additional clinical trials and seek FDA approval for pimavanserin as a broad-spectrum medication for multiple dementia subtypes. Second, rather than seeking broad-spectrum approval, the company could seek approval for pimavanserin as a medication for a smaller number of dementia subtypes such as Alzheimer's dementia or dementia with Lewy bodies, the subtypes for which the company believes they have the strongest data. Under this scenario, the company would not conduct additional clinical trials. Third, as is the FDA's position, the company could conduct additional clinical trials of pimavanesin in each dementia subtype.

The company has scheduled a meeting with the FDA to discuss the path forward for pimavanserin's development and expects to report on the outcome of this meeting before year end.

Despite the set backs regarding FDA approval, the trial results are an important step forward for clinical neuroscience and dementia research. Although the clinical trial results may be insufficient for FDA approval at present, they suggest that a badly needed safe and effective medication for dementia-related psychosis could come in the next few years.