Novel Drug First to Treat Negative Symptoms in Schizophrenia

Pam Harrison

September 09, 2015

AMSTERDAM — A novel antipsychotic that treats predominant persistent negative symptoms in schizophrenia and improves overall function is significantly more effective than standard antipsychotic therapy and is well tolerated, new phase 3 trial results indicate.

"What's important is that cariprazine was significantly more effective than risperidone [Risperdal, Janssen Pharmaceuticals, Inc] at not only improving symptoms but also the functionality of patients," George Nemeth, MD, PhD, chief medical officer, Gedeon Richter, Budapest, Hungary, told Medscape Medical News.

"And together, these two things could have a high impact on the patient's quality of life."

The study was presented here during the 28th European College of Neuropsychopharmacology (ECNP) Congress.

Double-Blind Trial

The multinational randomized, double-blind trial involved 461 patients with predominant, persistent negative symptoms of schizophrenia. The mean age of patients at study entry was 40 years, and the median time from diagnosis was 10.1 years.

At baseline, patients had a positive and negative syndrome scale negative factor score (PANSS-NFS) of 24 or greater and scored at least 4 on two of the three core negative symptoms. Core negative symptoms in schizophrenia include flat affect, social withdrawal, and apathy.

The baseline PANSS positive factor score (PANSS-PFS) was a maximum of 19. Patients had no clinically relevant depressive or extrapyramidal symptoms at baseline.

All patients had to be stabilized on prior medication and had to have predominant negative symptoms for 6 months prior to being screened for study enrollment and for an additional 4 weeks prior to randomization.

Patients were randomly assigned to receive either cariprazine or risperidone.

Following 2 weeks of cross-titration and discontinuation of prior antipsychotics, patients were treated with cariprazine, at a target dose of 4.5 mg a day, or to risperidone, at a target dose of 4 mg a day, for 6 months. Slightly more than three quarters of both groups completed the 6-month study.

From a baseline PANSS-NFS of approximately 27 in both treatment arms, the change from baseline at week 26 was significantly greater, at -8.9, in the cariprazine group compared with -7.4 for the risperidone control group (P = .002).

Dr Nemeth emphasized that the significant difference in negative symptoms between the two study agents was a reflection of a true effect of cariprazine on core negative symptoms and not the result of risperidone worsening negative symptoms relative to cariprazine.

At week 26, the change from baseline in the Personal and Social Performance Scale (PSP) of approximately 48 in each treatment group again showed significantly greater improvement with cariprazine, at a 14.3-point improvement, compared with risperidone, at a 9.7-point improvement, at study end point (P < .001).

The PSP scale is a measure of a patient's personal and social functioning.

There was also a statistically significant difference in the Clinical Global Impression score (CGI-S) in favor of cariprazine over risperidone at week 26 (P = .005), and more patients in the cariprazine group (69%) responded to treatment than did those in the risperidone group (58%) (P = .002).

Importantly, positive symptoms remained stable during the 6-month study regardless of whether patients were assigned to cariprazine or risperidone.

The most common nonpsychiatric adverse events during study treatment were insomnia and headache, both of which occurred in the risperidone control group.

The rates of discontinuation due to adverse events were low, at 10% for cariprazine and 12% for risperidone.

"Positive symptoms are what drive patients to the hospital, while negative symptoms are what drive patients to the street," Dr Nemeth said. "So this drug may have not only a significant clinical impact, but it may have a significant functional impact as well."

Convincing Data

Asked by Medscape Medical News to comment on the study, Wolfgang Fleischhacker, MD, professor of psychiatry, Medical University Innsbruck, in Austria, felt that the data comparing cariprazine with risperidone are convincing thus far.

"There was a statistically significant difference between two drugs in this indication, which has not been shown in previous large-scale trials where one antipsychotic beats another in patients suffering from predominant and persistent negative symptoms," Dr Fleischhacker said.

The fact that the new agent can be used as monotherapy to control both positive symptoms and improve negative symptoms is also an advantage, because it is always easier for patients to take a single drug, and monotherapy is the preferred treatment option if it works.

Dr Fleischhacker also confirmed that there is a definite need for a drug that specifically targets negative symptoms in schizophrenia.

"We did not have a drug that does this before, so cariprazine will be first in class," Dr Fleischhacker said. "It is a clinically important and highly relevant new development."

The study was supported by Gedeon Richter Plc. Dr Nemeth is the chief medical officer of Gedeon Richter. Dr Fleischhacker receives honoraria as well as research grants and serves as a consultant for a number of pharmaceutical companies, including Janssen and Lunbeck.

28th European College of Neuropsychopharmacology (ECNP) Congress. Abstract P.3.d.053. Presented August 31, 2015.

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