From the Editor

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

Up to 30% of patients with schizo- established a nonprofit foundation Henry A. Nasrallah, MD we called CURESZ (Comprehensive Editor-in-Chief phrenia do not respond to antagonists, which include all first- and Understanding via Research and Education in ), and assem- second-generation . bled a panel of 80 clozapine experts They are labeled as “treatment-resis- across the country to provide access to tant” if they have a partial response, clozapine for the hundreds of thousands Our clinical team or “treatment-refractory” if their hal- of individuals with refractory who never received a trial of clozapine made a serendipitous lucinations and/or delusions do not from their psychiatrists or psychiatric discovery about the improve at all despite multiple trials nurse practitioners. (Visit CURESZ.org of pimavanserin of antipsychotics. for details.) Bethany was very lucky to respond in patients with That’s why clozapine is considered and recover completely, because only schizophrenia who a “lifesaver” for such patients, a last- 40% of patients with refractory psycho- failed to respond to resort medication that unshackles sis respond to clozapine. She does not patients with refractory psychotic mind having her blood drawn every clozapine therapy symptoms from the tyranny of audi- week to measure her white blood cell tory and/or visual hallucinations and count for early detection of potentially the reality distortion of fixed false fatal agranulocytosis. Many refrac- beliefs such as paranoid delusions. tory, often homeless patients with Many long-suffering patients with chronic schizophrenia refuse to have refractory psychosis recover and return weekly phlebotomy and therefore are to their baseline, thanks to clozapine. In not treated with clozapine. Bethany a past editorial, I discussed how one of was also fortunate to experience only my patients, Bethany, who had dropped 1 adverse effect of clozapine: extreme out of college and became homeless for sedation that forced her to sleep up 4 years with refractory delusions and to 15 hours a day (this was reduced To comment on this hallucinations, recovered completely to 9 to 10 hours a day with adjunctive editorial or other topics when she received clozapine.1 She then modafinil). Fortunately, she was spared of interest: henry.nasrallah returned to college, graduated with the multiple other serious adverse @currentpsychiatry.com honors, and authored a book about her effects of clozapine, which include journey of recovery.2 She and I later excessive salivation, extreme weight continued on page 6 Current Psychiatry 4 April 2019 From the Editor

continued from page 4 Editorial Staff gain, diabetes, hyperlipidemia, car- at clinically adequate doses. Our EDITOR Jeff Bauer diomyopathy, pancreatitis, seizures, findings were published online last SENIOR EDITOR Sathya Achia Abraham and ileus.3 Clozapine is also associ- month in the highly respected journal ASSISTANT EDITOR Jason Orszt 8 WEB ASSISTANTS ated with sudden death more than any Schizophrenia Research. We reported the Tyler Mundhenk, Kathryn Wighton other agent.4 successful treatment with pimavanse- Art & Production Staff So, what can be done for patients rin in 2 groups: CREATIVE DIRECTOR Mary Ellen Niatas with refractory hallucinations and delu- • patients who had not responded ART DIRECTOR Pat Fopma DIRECTOR, JOURNAL MANUFACTURING sions who are among the 60% who fail to clozapine received pimavanserin as Michael Wendt to respond to clozapine, or who experi- an add-on to clozapine in doses of 34 PRODUCTION MANAGER Donna Pituras ence intolerable adverse effects or safety mg/d, the same dose recommended Publishing Staff problems, or who refuse to take clozap- for patients with Parkinson’s disease Sharon Finch PUBLISHER ine and have their blood drawn every hallucinations and/or delusions. DIRECTOR eBUSINESS DEVELOPMENT Alison Paton week? This is a desperately ill and seri- • patients who had hallucinations SENIOR DIRECTOR OF SALES Tim LaPella ously disabled group of patients who are and delusions that failed to respond to CONFERENCE MARKETING MANAGER deemed to be beyond the reach of medi- several non-clozapine antipsychotics Kathleen Wenzler cal intervention by psychiatry. They are received pimavanserin monotherapy Editor-in-Chief Emeritus often treated with various off-label med- instead of clozapine to avoid blood James Randolph Hillard, MD ications as adjunctive therapy to clozap- draws and serious adverse effects. Frontline Medical Communications ine, to which they failed to respond. This Pimavanserin successfully treated PRESIDENT/CEO Alan J. Imhoff includes adding lamotrigine5 or benzo- the hallucinations and delusions of all CFO Douglas E. Grose ate,6 but none have been approved as 10 patients in both groups. Remission SVP, FINANCE Steven Resnick VP, OPERATIONS Jim Chicca an efficacious and safe monotherapy occurred within 1 month in most cases, VP, SALES Mike Guire alternative to clozapine. So, what can be and after 2 months in 1 patient. Those VP, SOCIETY PARTNERS Mark Branca done for patients with refractory illness? patients no longer required hospitaliza- VP, EDITOR IN CHIEF Mary Jo Dales VP, EDITORIAL DIRECTOR, CLINICAL CONTENT Enter pimavanserin. This new med- tion as they did prior to taking pima- Karen Clemments ication is an of sero- vanserin, and they maintained their CHIEF DIGITAL OFFICER Lee Schweizer VP, DIGITAL CONTENT & STRATEGY tonin 5-HT2A receptors and (to a lesser response for several months of follow- Amy Pfeiffer extent) 5-HT2C receptors. It up. We were also pleased to note that PRESIDENT, CUSTOM SOLUTIONS JoAnn Wahl was recently FDA-approved for treat- most patients became more sociable and VP, CUSTOM SOLUTIONS Wendy Raupers VP, MARKETING & CUSTOMER ADVOCACY ing the hallucinations and delusions of affable, with improved mood and affect, Jim McDonough Parkinson’s disease psychosis,7 which after their hallucinations and delusions VP, HUMAN RESOURCES & FACILITY OPERATIONS Carolyn Caccavelli is estimated to develop in up to 50% of disappeared with pimavanserin. We did DATA MANAGEMENT DIRECTOR Mike Fritz individuals with Parkinson’s disease. It have a few patients who did not respond CIRCULATION DIRECTOR Jared Sonners does not have any affinity to any dopa- to 34 mg/d of pimavanserin, and some CORPORATE DIRECTOR, RESEARCH & COMMUNICATIONS Lori Raskin mine receptors, which makes it an ideal who responded for several months but DIRECTOR, CUSTOM PROGRAMS Patrick Finnegan antipsychotic for Parkinson’s disease, then showed signs of recurrence. We are where any dopamine antagonism can considering increasing the dose to 68 In affiliation with Global Academy for Medical Education, LLC worsen the motor symptoms (rigid- mg/d in such patients because it is pos- PRESIDENT David J. Small, MBA ity, hypokinesia, and tremors) associ- sible that a higher dose may be needed ated with that movement disorder. in some patients with refractory illness, Thus, pimavanserin became the first who may vary in symptom severity

7 Century Drive, Suite 302 ever non-dopaminergic antipsychotic or biology. Parsippany, NJ 07054 in the world and is indicated only for We are now planning to apply for a Tel: (973) 206-3434 Fax: (973) 206-9378 Parkinson’s disease psychosis. research grant to conduct a controlled www.frontlinemedcom.com Our clinical team made a serendipi- trial to confirm our very encouraging Subscription Inquiries: [email protected] tous discovery about the efficacy of clinical findings, and we hope other pimavanserin in patients with schizo- investigators will also conduct clinical Published through an educational partnership phrenia who failed to respond to clo- trials in patients with refractory psy- with Saint Louis University zapine therapy after several months chosis comparing pimavanserin with continued on page 8 Current Psychiatry 6 April 2019 From the Editor

continued from page 6 placebo or pimavanserin with clozap- References 1. Nasrallah HA. Clozapine is a vastly underutilized, ine in double-blind studies. unique agent with multiple applications. Current As a disclosure, our clinical findings Psychiatry. 2014;13(10):21, 24-25. 2. Yeiser B. Mind estranged: my journey from were obtained without any knowl- schizophrenia and homelessness to recovery. edge of, or funding from, the company Seattle, WA: Amazon; 2014. 3. Raja M, Raja S. Clozapine safety, 40 years later. that makes pimavanserin (Acadia Curr Drug Saf. 2014;9(3):163-195. Pharmaceuticals Inc.). The company 4. Manu P, Kane JM, Corell CU. Sudden deaths in psychiatric patients. J Clin Psychiatry. 2011;72(7): was informed of our findings only after 936-941. our article was accepted for publication. 5. Tiihonen J, Wahlbeck K, Kiviniemi V. The I hope this important finding of a efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta- potentially safer alternative to clozap- analysis. Schizophrenia Research. 2009;109(1-3): ine may address a major unmet need in 10-14. 6. Lin CH, Lin CH, Chang YC, et al. Sodium psychiatry, involving the treatment of benzoate, a D-amino acid oxidase inhibitor, added hundreds of thousands of patients with to clozapine for the treatment of schizophrenia: Pimavanserin a randomized, double-blind, placebo-controlled treatment-resistant or treatment-refrac- trial. Biol Psychiatry. 2017;84(6):422-432. successfully treated tory psychosis, which includes patients 7. Ballard C, Banister C, Khan Z, et al; ADP Investigators. Evaluation of the safety, tolerability, the hallucinations with schizophrenia, schizoaffective dis- and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a order, or psychotic bipolar disorder. phase 2, randomised, placebo-controlled, double- and delusions of all 10 blind study. Lancet Neurol. 2018;17(3):213-222. 8. Nasrallah HA, Fedora R, Morton R. Successful patients in both groups treatment of clozapine-nonresponsive refractory hallucinations and delusions with pimavanserin, a serotonin 5HT-2A receptor inverse agonist [Epub Henry A. Nasrallah, MD ahead of print March 2, 2019]. Schizophrenia Res. Editor-in-Chief 2019. doi: 10.1016/j.schres.2019.02.018.

Current Psychiatry 8 April 2019