Relapse in Patients with Dementia-Related Psychosis After Discontinuation of Pimavanserin

February 2022

Psychosis may occur in people with dementia, leading to difficulties for caregivers and poorer outcomes for patients. Antipsychotics may be harmful in these patients, and clinical guidelines recommend minimizing their use in patients with dementia.

Pimavanserin is an oral atypical antipsychotic that is an inverse agonist and antagonist of the serotonin receptor 2A. In previous clinical trials for psychosis in patients with Parkinson disease or Alzheimer disease, pimavanserin appeared to be more efficacious in patients with more severe psychosis.

The HARMONY study was a phase 3 randomized discontinuation trial. Investigators wanted to know whether pimavanserin therapy in patients with psychosis and dementia could be discontinued without a relapse of psychosis. “This design addresses the question of whether treatment with pimavanserin would confer sustained benefits with respect to psychosis in patients with an initial response to the drug; the design also translates to decisions about medication discontinuation and minimizes exposure to ineffective therapy,” the investigators explained.

All participants in the HARMONY trial received a diagnosis of dementia (possible or probable Alzheimer disease, Parkinson dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia) with psychotic symptoms that lasted for at least 2 months. They received open-label pimavanserin for 12 weeks. Responders in the open-label period were defined as those with at least a 30% improvement in score on the Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions and a rating of much improved or very much improved on the Clinical Global Impression–Improvement scale at weeks 8 and 12.

Responders then entered a double-blind randomized treatment period for continuation of pimavanserin or placebo for 26 weeks. The primary outcome was time to relapse of psychosis, and the secondary outcome was time to all-cause discontinuation.

There were 351 patients who completed the open-label period and were eligible to enter the double-blind period. At the end of the open-label period, the investigators identified 61.8% of patients who responded to pimavanserin with improvements in assessments of psychosis. These responders were randomized to receive pimavanserin (105 patients) or placebo (112 patients) in the double-blind period of the trial.

The double-blind period was stopped early for efficacy after an interim analysis. Significantly more patients in the placebo group had relapsed compared with the pimavanserin group (28% vs 13%; P = .005). Discontinuation of treatment for any reason occurred in 38% of patients in the placebo group compared with 22% in the pimavanserin group (P = .005). The most common reason for treatment discontinuation in both groups was relapse of psychosis.

Headache, constipation, and urinary tract infections were more common in the pimavanserin group than in the placebo group.

In this study, relapse of psychosis was found within a few months of discontinuation. It is unclear how long patients would need to take pimavanserin to prevent psychosis. “Longer and larger trials are required to determine the effects of pimavanserin in dementia-related psychosis,” the investigators stated.


Tariot PN, Cummings JL, Soto-Martin ME, et al. Trial of pimavanserin in dementia-related psychosis. N Engl J Med. 2021;385:309-319.

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