Adjunctive treatment with the atypical antipsychotic pimavanserin (Nuplazid, Acadia Pharmaceuticals) is associated with significant improvement in patients with schizophrenia who have predominantly negative symptoms, new research suggests.
The drug, which is approved by the US Food and Drug Administration (FDA) to treat hallucinations and delusions associated with Parkinson's disease psychosis, was effective, safe and well tolerated.
"Approximately 40% to 50% of schizophrenia patients suffer from predominant negative symptoms, and there are no approved treatments," presenting author Dragana Bugarski-Kirola, MD, vice president for clinical development at Acadia Pharmaceuticals, told Medscape Medical News.
The findings were presented at the American Society of Clinical Psychopharmacology (ASCP) 2020 Virtual Conference.
No Approved Treatment
Negative symptoms are core symptoms of schizophrenia but are often not recognized because they have "a slow and insidious development," said Bugarski-Kirola.
They are characterized by a gradual loss interest, motivation, lack of emotional reactivity, blunted affect, and gradual decrease in communication. In contrast, positive symptoms such as delusions or agitation are more visible, and as such are often easier to spot in a patient with schizophrenia, Bugarski-Kirola added.
Negative symptoms have detrimental long-term consequences and require long-term treatment so patients can reestablish self-care and social networks; thus, there is a large need for an effective treatment.
Previous research suggests adjunctive pimavanserin may be effective in schizophrenia, including a potential beneficial effect on negative symptoms.
The randomized placebo-controlled trial included 403 stable schizophrenia outpatients with predominant negative symptoms who were randomly assigned to receive either once-daily pimavanserin (n = 201) or placebo (n = 202) as an adjunct to current antipsychotic treatment .
Participants' mean age was 37.2 years; most (87.8%) patients were from European sites and the rest were from North America.
The initial dose was 20 mg, and dose adjustments were allowed to 34 mg or to 10 mg during the first 8 weeks of treatment. The final dose of pimavanserin was 34 mg in 53.8% of patients, 20 mg in 44.7%, and 10 mg in 1.5%.
The trial's primary endpoint was change from baseline to week 26 on the Negative Symptom Assessment-16 (NSA-16) total score.
"The NSA-16 is a validated tool for measuring the severity of negative symptoms. It evaluates 16 items that comprehensively assess the condition and includes the following factors: communication, emotion and affect, social involvement, motivation, and retardation," Bugarski-Kirola said.
Addition of pimavanserin led to overall improvement of negative symptoms that became evident early in the study.
At 26 weeks, significant improvement was observed for the NSA-16 total score with pimavanserin vs placebo (–10.4 vs –8.5; P = .043; effect size = 0.21).
A greater improvement in the NSA-16 total score compared with placebo was observed in the patients who received the highest pimavanserin dose of 34 mg (–11.6 vs –8.5; unadjusted P = .0065, effect size = 0.34).
Pimavanserin was well tolerated with high completion rates of approximately 86% in both the pimavanserin and placebo groups, and similar rates of adverse events between pimavanserin (39.8%) and placebo (35.1%).
The most frequent adverse events were headache (6.5% pimavanserin, 5% placebo) and somnolence (5.5% pimavanserin, 5% placebo). Serious adverse events, reported as worsening of schizophrenia, occurred in 2% of patients on pimavanserin and 0.5% of patients on placebo.
A phase 3 study will be launched in the next few months, Bugarski-Kirola said.
"This is very encouraging," Christoph Correll, MD, professor of child and adolescent psychiatry, Charité Universitatsmedizin, Berlin, Germany, told Medscape Medical News.
"Negative symptoms of schizophrenia have been pretty much unaddressed since we have had antipsychotics. Some of the very tight binding agents can actually make negative symptoms worse," said Correll, who was not part of the study.
"The second generation agents don't do this as much, yet they don't seem to have a primary effect on negative symptoms, so having an adjunctive agent that can be given with existing antipsychotics that cover positive symptoms to a large degree, and then further improve negative symptoms, would be a huge asset," explained Correll, who has a joint appointment as professor of psychiatry and molecular medicine at the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York.
However, he cautioned that there have been many phase 2 studies that, when translated into larger phase 3 trials, do not replicate the early results.
"They should perhaps explore a higher dose if they can because they had such good safety at the lower dose, and there seems to be a 'dose–response' relationship. We really look forward to more data," Correll said.
The study was funded by Acadia Pharmaceuticals Inc. Bugarski-Kirola is vice president for clinical development of Acadia Pharmaceuticals. Correll reports that he has been a consultant and/or advisor to or has received honoraria from Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, Intra-Cellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Nejurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva.
American Society of Clinical Psychopharmacology (ASCP) 2020: Abstract 3002487. Presented May 30, 2020.
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Cite this: Antipsychotic May Fill SchizophreniaTreatment Need - Medscape - Jun 05, 2020.