From the Editor

Pimavanserin: A potentially safer alternative to clozapine for refractory hallucinations and delusions

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Up to 30% of patients with schizophrenia do not respond to dopamine antagonists, which include all first- and second-generation antipsychotics. They are labeled as “treatment-resistant” if they have a partial response, or “treatment-refractory” if their hallucinations and/or delusions do not improve at all despite multiple trials of antipsychotics.

That’s why clozapine is considered a “lifesaver” for such patients, a last-resort medication that unshackles patients with refractory psychotic symptoms from the tyranny of auditory and/or visual hallucinations and the reality distortion of fixed false beliefs such as paranoid delusions.

Many long-suffering patients with refractory psychosis recover and return to their baseline, thanks to clozapine. In a past editorial, I discussed how one of my patients, Bethany, who had dropped out of college and became homeless for 4 years with refractory delusions and hallucinations, recovered completely when she received clozapine.1 She then returned to college, graduated with honors, and authored a book about her journey of recovery.2 She and I later established a nonprofit foundation we called CURESZ (Comprehensive Understanding via Research and Education in Schizophrenia), and assembled a panel of 80 clozapine experts across the country to provide access to clozapine for the hundreds of thousands of individuals with refractory psychosis who never received a trial of clozapine from their psychiatrists or psychiatric nurse practitioners. (Visit for details.)

Bethany was very lucky to respond and recover completely, because only 40% of patients with refractory psychosis respond to clozapine. She does not mind having her blood drawn every week to measure her white blood cell count for early detection of potentially fatal agranulocytosis. Many refractory, often homeless patients with chronic schizophrenia refuse to have weekly phlebotomy and therefore are not treated with clozapine. Bethany was also fortunate to experience only 1 adverse effect of clozapine: extreme sedation that forced her to sleep up to 15 hours a day (this was reduced to 9 to 10 hours a day with adjunctive modafinil). Fortunately, she was spared the multiple other serious adverse effects of clozapine, which include excessive salivation, extreme weight gain, diabetes, hyperlipidemia, cardiomyopathy, pancreatitis, seizures, and ileus.3 Clozapine is also associated with sudden death more than any other antipsychotic agent.4

So, what can be done for patients with refractory hallucinations and delusions who are among the 60% who fail to respond to clozapine, or who experience intolerable adverse effects or safety problems, or who refuse to take clozapine and have their blood drawn every week? This is a desperately ill and seriously disabled group of patients who are deemed to be beyond the reach of medical intervention by psychiatry. They are often treated with various off-label medications as adjunctive therapy to clozapine, to which they failed to respond. This includes adding lamotrigine5 or benzoate,6 but none have been approved as an efficacious and safe monotherapy alternative to clozapine. So, what can be done for patients with refractory illness?

Enter pimavanserin. This new medication is an inverse agonist of serotonin 5-HT2A receptors and (to a lesser extent) serotonin 5-HT2C receptors. It was recently FDA-approved for treating the hallucinations and delusions of Parkinson’s disease psychosis,7 which is estimated to develop in up to 50% of individuals with Parkinson’s disease. It does not have any affinity to any dopamine receptors, which makes it an ideal antipsychotic for Parkinson’s disease, where any dopamine antagonism can worsen the motor symptoms (rigidity, hypokinesia, and tremors) associated with that movement disorder. Thus, pimavanserin became the first ever non-dopaminergic antipsychotic in the world and is indicated only for Parkinson’s disease psychosis.

Our clinical team made a serendipitous discovery about the efficacy of pimavanserin in patients with schizophrenia who failed to respond to clozapine therapy after several months at clinically adequate doses. Our findings were published online last month in the highly respected journal Schizophrenia Research.8 We reported the successful treatment with pimavanserin in 2 groups:

  • patients who had not responded to clozapine received pimavanserin as an add-on to clozapine in doses of 34 mg/d, the same dose recommended for patients with Parkinson’s disease hallucinations and/or delusions.
  • patients who had hallucinations and delusions that failed to respond to several non-clozapine antipsychotics received pimavanserin monotherapy instead of clozapine to avoid blood draws and serious adverse effects.

Continue to: Pimavanserin successfully treated...


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