VIENNA – Cariprazine appears to improve predominant negative symptoms of schizophrenia as well as functional status in affected patients, István Bitter, MD, PhD, DSci reported at the annual congress of the European College of Neuropsychopharmacology.

Cariprazine, a dopamine D₃/D2 receptor partial agonist, was approved in the United States in 2015 as Vraylar for adults with bipolar disorder or schizophrenia. The drug remains investigational in Europe.

A drug with a specific indication for treatment of prominent and persistent negative symptoms in patients with chronic schizophrenia has been a long-sought and thus far elusive goal. It would be a major advance. More than half of schizophrenia patients in outpatient clinics display prominent negative symptoms. These patients tend to have a poor response to traditional antipsychotic agents, and their clinical outcome is poor as well, noted Dr. Bitter, professor of psychiatry at Semmelweis University in Budapest.

“There is very clearly an unmet need for the treatment of deficit schizophrenia, or schizophrenia with predominant and persistent negative symptoms,” the psychiatrist observed.

The strong efficacy signal for cariprazine in patients with predominant negative symptoms was identified in a post hoc analysis of a randomized, double-blind, phase III head-to-head comparison of cariprazine versus risperidone (Risperdal) in 461 affected adults. Dr. Bitter was a coinvestigator in the 26-week multicenter European study, which was preceded by a 4-week lead-in phase in which participants were uptitrated to a target dose of cariprazine at 4.5 mg/day or risperidone at 4 mg/day.

The primary endpoint in the post hoc analysis was change from baseline on the Positive and Negative Symptoms Factor Score for Negative Symptoms (PANSS-FSNS). A significant difference in favor of cariprazine was seen by week 14, and the gap steadily enlarged thereafter through the remainder of the study. The difference was significant in five of the seven items on the PANSS-FSNS: blunted affect, emotional withdrawal, poor rapport, active social avoidance, and passive/apathetic social withdrawal. Cariprazine also outperformed risperidone on the other two elements of the scale – motor retardation, and lack of spontaneity and flow of conversation – but in those domains, the difference didn’t reach statistical significance.

Patients randomized to cariprazine also fared well on secondary endpoints. They displayed a significantly greater overall improvement in Marder factor scores over 26 weeks than the risperidone-treated group. This advantage was driven by a strong, statistically significant difference in the domain of difficulty in abstract thinking. However, the cariprazine group also showed nonsignificant trends for greater improvement in conceptual disorganization, mannerisms and posturing, disorientation, poor attention, and disturbed volition.

As evidence that cariprazine was exerting specific benefit on negative symptoms, Dr. Bitter cited the fact that the drug showed no significant difference from risperidone in change from baseline on the Marder factor scores for uncontrolled hostility/excitement and anxiety/depression, nor in the Calgary Depression Rating Scale for Schizophrenia.

Regulatory agencies in the United States and Europe have made it clear that, for a drug to obtain an indication for treatment of predominant negative symptoms of schizophrenia, it also has to show evidence of improved patient social function. The cariprazine group showed a significantly greater improvement on the PANSS-FSNS Personal and Social Performance Score. This advantage over risperidone-treated patients reached statistical significance at week 10 and broadened thereafter until study conclusion. Improvements in the subdomain scores for self-care, socially useful activities, and personal and social relationships led the way.

These positive results for cariprazine represent a sharp departure from the psychiatric field’s long-standing history of failed therapeutic attempts to improve negative symptoms. A comprehensive 2015 meta-analysis of all 168 randomized, placebo-controlled studies of various potential treatments for predominant negative symptoms of schizophrenia published through 2013 concluded that none of them provided evidence of clinically meaningful improvement (Schizophr Bull. 2015 Jul;41[4]:892-9).

Dr. Bitter observed that, since that discouraging meta-analysis, several additional novel agents for treatment of predominant negative symptoms of schizophrenia that showed “fantastic” promise in phase II studies subsequently went down in flames in advanced phase III trials. Among those were D-serine as an add-on to second-generation antipsychotics; encenicline, an alpha-7 nicotinic acetylcholine receptor antagonist; pomaglumetad methionil, a selective agonist for glutamate receptor subtypes mGluR2 and mGluR3; and bitopertin, a glycine reuptake inhibitor.

“This is basically a very negative message, that there is not much we can do about negative symptoms. But depending on who you ask, you can get a little bit more optimistic picture,” Dr. Bitter said.

That’s because there are considerable differences among the studies both in how negative symptoms are defined as well as in the measurement tools employed. For example, the Scale for Assessment of Negative Symptoms (SANS) includes items which aren’t strictly speaking part of the negative symptoms concept, so it yields skewed results. The Brief Psychiatric Rating Scale is a relic that has been abandoned by younger psychiatrists. So at present, the PANS-FSNS is the best available tool, and a reasonable common sense definition of predominant negative symptoms of schizophrenia is that, in an affected patient, the PANSS negative subscale score is higher than the positive one, he continued.

It’s noteworthy that none of the multitude of failed drugs for negative symptoms of schizophrenia target activity of dopamine-3 receptors. But cariprazine does.

“There is hope that dopamine-3 receptors might play a role in schizophrenia, especially in negative symptoms. According to experts, they are much older by a couple of million years than the D₂ receptors. They don’t operate like D₂. In fact, their function is not very clear. In animal studies, though, they help with cognition,” Dr. Bitter said.

In view of the dismal track record of prior therapeutic efforts, session cochair Maria Ferrara, MD, president-elect of the European Psychiatric Association, was guardedly optimistic about dopamine-3 receptors as a therapeutic target in predominant negative symptoms of schizophrenia.

“These cariprazine results open the door to some hope for the future,” commented Dr. Ferrara, professor of psychiatry at the University of Naples, Italy.

Even so, she added in an interview, most clinicians aren’t ready to handle a drug with an indication for treatment of negative symptoms. “We are not ready as clinicians to rate negative symptoms in our patients, or in many, many cases to even recognize them. In my opinion, several promising drugs failed because of the fact that the evaluations were not very well carried out in spite of training, but also because, so far, the assessment instruments have not been the best you could think of. Clinicians need training, and the assessment instruments need to be refined. We need instruments that provide more in-depth evaluation of the different aspects of negative symptoms and that are also more appealing to clinicians,” according to the psychiatrist.

She agreed with Dr. Bitter that, for now, the PANSS-FSNS is the best available assessment tool.

“The SANS is not a good tool for negative symptoms. We are all sure about that. We can and should do better,” Dr. Ferrara said.

The cariprazine study was funded by Gedeon Richter and Allergen. Dr. Bitter reported serving as an advisory board member and/or consultant to Gedeon Richter and eight other pharmaceutical companies.

bjancin@frontlinemedcom.com

Cariprazine shows efficacy for schizophrenia’s negative symptoms