Pimavanserin may reduce negative symptoms of schizophrenia

A 26-week, randomized, double-blind, placebo-controlled phase 2 study showed pimavanserin reduced negative schizophrenia symptoms in stable patients.

Researchers noted that further study with improved doses of the drug is required to determine if the results are clinically significant.

“Negative symptoms were alleviated in a case series of 10 patients with schizophrenia who were treated with pimavanserin,” Dragana Bugarski-Kirola, MD, of Acadia Pharmaceuticals GmbH in Switzerland, and colleagues wrote in The Lancet Psychiatry. “Based on data from compounds with similar receptor profiles, we hypothesized that pimavanserin provides additional benefit in adults with negative symptoms of schizophrenia whose treatment benefit has been maximized on ongoing second-generation antipsychotics via its additional effects on neocortical dopamine release.

“The phase 2 ADVANCE trial evaluated efficacy and safety of adjunctive pimavanserin compared with placebo in adults with schizophrenia and predominant negative symptoms while on optimized background antipsychotic therapy,” they added.

Between Nov. 4, 2016, and April 16, 2019, the investigators randomly assigned 403 outpatients with schizophrenia who were aged 18 to 55 years old with predominant negative symptoms to pimavanserin or placebo daily in combination with an ongoing antipsychotic agent.

The study took place across 83 sites in North America and Europe. Participants scored at least 20 on the sum of seven Positive and Negative Syndrome Scale (PANSS) Marder negative factor items, with scores of four or higher on at least three or five or higher on at least two of negative symptom items. The initial dosage of 20 mg of the drug or placebo could be changed to 34 mg or 10 mg within the study’s first 8 weeks, after which dosage remained stable for the study’s duration. Patients received pimavanserin and placebo orally once per day as two individual tablets. Change in total score using the 16-item Negative Symptom Assessment (NSA-16) between baseline and 26 weeks served as the primary endpoint. The researchers examined primary outcomes among patients who received at least one dose of pimavanserin and who had NSA-16 assessments at baseline and one or more times after baseline. They assessed safety outcomes among patients who had received at least one dose of pimavanserin.

In the efficacy analysis, Bugarski-Kirola and colleagues included 400 patients. A total of 199 received pimavanserin (mean age, 37.7 years) and 201 received placebo (mean age, 36.7 years). Results showed pimavanserin was associated with significant improvement in change in total NSA-16 score between baseline and 26 weeks compared with placebo.

Researchers found the number of participants who experienced treatment-emergent adverse events over the 26-week course was similar between those given the drug (n = 80) vs. those given placebo (n = 71). Headache and somnolence represented the most common treatment-emergent adverse events. Only one participant in the placebo group reported severe symptoms, while two in the pimavanserin group were found to have increased severity of schizophrenia symptoms. Severe headache, rhinorrhoea, cough and influenza occurred among one patient in the placebo group. Among the pimavanserin group, one patient reported severe toothache and two patients reported worsening of schizophrenia. Pimavanserin correlated with higher mean change in QTcF interval.

“Amidst an unmet need for safe and effective treatments for negative symptoms of schizophrenia, pimavanserin added to ongoing antipsychotic treatment resulted in a significant improvement in negative symptoms of schizophrenia and was well tolerated,” Bugarski-Kirola and colleagues wrote. “Treatment efficacy for negative symptoms of schizophrenia was influenced by patients who received pimavanserin 34 mg and was the greatest in men, patients from Europe, those with pronounced symptom severity than those with mild or moderate symptoms and those who had had schizophrenia and negative symptoms for more than 5 years.

“Although the primary outcome was statistically significant, further studies are needed to optimize dosing and determine the clinical significance of pimavanserin for the treatment of negative symptoms in schizophrenia,” they added.