Table of Contents

Volume 2, Issue 6                                                                                              June, 2016

New Drug Update:

Brexpiprazole (Rexulti) and Pimavanserin (Nuplazid)

New antipsychotics with novel mechanisms

This month PL highlights two new antipsychotics recently on the market in the US.  The first, brexpiprazole, is a partial dopamine agonist, like aripiprazole, but with some differences.  The second, pimavanserin, is an “inverse serotonin agonist,” without any dopamine blockade at all, just approved for treatment of psychosis in Parkinson’s disease.  


Biological mechanism

This agent is a dopamine blocker but it also has dopamine agonism. This basic mechanism is similar to aripiprazole. The difference is a matter of potency. As usual, the D2 blockade is dose dependent, such that eventually, over 90% of D2 receptors are blocked.  This level of D2 blockade produces extrapyramidal symptoms (EPS) such as akathisia, which may remain the main clinical problem with this agent, as with the entire dopamine blocker class. 

The dopamine agonism of this agent is somewhat less than occurs with aripiprazole. In animal studies, there was 43% agonism for brexpiprazole compared to 61% for aripiprazole. The relevance of this distinction may be that brexpiprazole may have less of some of the dopamine stimulation effects that are seen with aripiprazole, which may be observed clinically in terms of mania induction or possibly reduced antipsychotic potency.  

Like aripiprazole and other new antipsychotics, brexpiprazole does not appear to cause or worsen the metabolic syndrome of diabetes, hypertension, and hyperlipidemia. 

Clinical efficacy

Unlike most other antipsychotics, brexpiprazole was not initially indicated for the classic antipsychotic indications of schizophrenia and mania.  Instead, it was developed to be indicated by the FDA indications for schizophrenia and for MDD as an adjunct to SRIs. It has not yet been studied for mania or bipolar depression.  


2-4 mg/d are proven effective for the above indications. 


Biological mechanism

This agent is the first proven antipsychotic that does not cause dopamine blockade.  A number of prior putative antipsychotics, which were not dopamine blockers, have been studied over the years; most of those agents were pure serotonin blockers.  When studied in clinical trials, though, those agents didn’t work.  This agent appears to be the first to have proven some clinical efficacy, in this case for psychotic symptoms in Parkinson’s disease.  The purported mechanism of pimavanserin is “inverse agonism” of the serotonin 1A receptor.  This mechanism is thought to result in complete blockade of serotonin activity at that receptor, as opposed to other prior serotonin blockers, which still allowed for a small amount of activity at that receptor. Whether this mechanism truly explains the antipsychotic efficacy of this agent remains to be seen. 

Clinical efficacy

For now, this medication is only FDA indicated for psychosis in Parkinson’s disease.  However, a randomized trial in schizophrenia has shown efficacy over placebo.  We’ll need to see if that efficacy is replicated and then followed by FDA indication.  If this occurs, this would be a major shift in treatment of severe psychosis in schizophrenia, as well as possibly for mania or bipolar illness, since this agent would be the first non-dopamine blocker that would be effective for classic psychosis. 

Dosing and other features

The effective dose is 34 mg/d for Parkinson’s psychosis, with pill sizes of 17 mg per pill.  This agent has a very long half life of 2 1/2 days. Thus it would take 1-2 weeks to achieve a steady state, if not longer in older persons with Parkinson’s disease. This feature of this medication should be kept in mind.  

Side Effects

The main observed side effect in the clinical trials in Parkinson’s disease was peripheral edema. There was no weight gain or metabolic syndrome. 

The PL Bottom Line

  • Brexpiprazole is proven effective for schizophrenia and as an adjunct for MDD. It has somewhat less dopamine agonism than aripiprazole.  
  • Brexpiprazole has minimal weight gain and no apparent risk of metabolic syndrome or worsening diabetes or cardiovascular risks. Akathisia remains a potential important risk. 
  • Pimavanserin is a pure serotonin blocker which is proven effective for psychosis in Parkinson’s disease.It does not cause extrapyramidal side effects.  
  • Pimavanserin has a very long half-life of 2-3 days.  

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