In short
Pimavanserin is a chemical, investigational substance studied in psychiatry. It is being tested in one Phase 2 trial with 60 participants to see if it can block the psychedelic effects of psilocybin while preserving its antidepressant action in major depressive disorder. Pimavanserin is already approved in the United States as an atypical antipsychotic for hallucinations and delusions in Parkinson's disease psychosis, but in this trial it is being explored for a completely different purpose.
Key points
- Pimavanserin is an atypical antipsychotic approved for Parkinson's disease psychosis, but is being tested for a new purpose in major depressive disorder.
- The only trial in the registry is a Phase 2 study with 60 participants.
- The trial compares psilocybin plus pimavanserin against psilocybin plus placebo.
- The main goal is to measure changes in brain connectivity using functional MRI.
- The study is currently authorised but not yet reporting results.
- Pimavanserin is given as a 34 mg oral tablet in the trial.
What is pimavanserin?
Pimavanserin is a chemically synthesised substance that belongs to the group of medicines called atypical antipsychotics. It is also known by the brand name Nuplazid and the product name pimavanserin tartrate. In the United States, pimavanserin has been approved since 2016 for treating hallucinations and delusions associated with Parkinson's disease psychosis. In the European trial registry records, however, pimavanserin appears as an investigational substance with no marketing authorisation, and it is being studied for a different condition: major depressive disorder.
How does pimavanserin work?
Pimavanserin works by acting on a specific receptor in the brain called the serotonin 5-HT2A receptor. It is described as an inverse agonist and antagonist at this receptor, meaning it reduces the receptor's activity. This is thought to help balance substances in the brain that regulate mood, behaviours, and thoughts. In the current trial, researchers are testing whether this same receptor-blocking action can prevent the psychedelic experience caused by psilocybin while still allowing psilocybin's potential antidepressant effects to occur.
Which conditions is it used or studied for?
- Parkinson's disease psychosis — pimavanserin is an approved medicine for hallucinations and delusions in people with Parkinson's disease.
- Major depressive disorder — the trial in the registry is testing pimavanserin as a way to block the psychedelic effects of psilocybin in people with major depressive disorder.
How is pimavanserin given?
Pimavanserin is taken by mouth. The approved product is available as capsules of 34 mg and tablets of 10 mg. The product information gives a 34 mg once-daily oral dose, without the need to gradually increase the dose, and it can be taken with or without food. In the European trial, pimavanserin tartrate is given as a 34 mg oral tablet.
What do the clinical trials show?
The registry contains one trial of pimavanserin, a Phase 2 interventional study with 60 participants. The trial is authorised but has not yet reported results. It is investigating whether pimavanserin can separate the antidepressant effects of psilocybin from its psychedelic experience in people with major depressive disorder.
Participants are divided into two groups: one receives psilocybin plus pimavanserin, and the other receives psilocybin plus placebo. The main measurement is changes in resting-state network functional connectivity in the brain, assessed with functional magnetic resonance imaging across three scans. The trial does not list detailed eligibility criteria in the registry record, but it is focused on patients with major depressive disorder.
What side effects are known?
The most common side effects reported with pimavanserin in its approved use are peripheral edema (swelling, especially in the legs) and confusional state. Pimavanserin can also prolong the QT interval, a measure of the heart's electrical activity, which may increase the risk of irregular heart rhythms. A boxed warning states that elderly patients with dementia-related psychosis treated with antipsychotic drugs, including pimavanserin, are at an increased risk of death. In a Phase 3 comparison with quetiapine in Parkinson's disease psychosis, pimavanserin was reported to be very well tolerated and did not worsen motor symptoms.
Does pimavanserin interact with other medicines?
Pimavanserin is broken down in the body by an enzyme called CYP3A4. Strong inhibitors of this enzyme can increase pimavanserin levels, and the product information recommends reducing the pimavanserin dose to 10 mg once daily when used with strong CYP3A4 inhibitors. Strong or moderate CYP3A4 inducers should be avoided, as they can lower pimavanserin levels. Because pimavanserin can prolong the QT interval, it should generally be avoided with other medicines that also prolong the QT interval.