Nancy A. Melville

June 19, 2017

MIAMI – The antipsychotic cariprazine shows evidence of accomplishing something no other antipsychotic has been capable of ― improving the negative symptoms common in patients with psychosis and schizophrenia.

"Negative symptoms in psychosis or schizophrenia have been a very important clinical target for the last several years, and there is currently no drug in the US with efficacy to treat the symptoms," said study investigator Nina R. Schooler, PhD, of the SUNY Downstate Medical Center, New York City.

"The data in this study are quite convincing, and if confirmed and the findings translate to successful treatment, that would be incredibly important," Dr Schooler told Medscape Medical News.

The study was presented here at the American Society of Clinical Psychopharmacology (ASCP) 2017 Annual Meeting.

Important Treatment Goal

Negative symptoms common to schizophrenia and psychosis include apathy, lack of emotion, and poor social functioning. The lack of an effective treatment represents a significant problem with respect to quality of life for patients whose other symptoms of psychosis can usually be managed by medication.

"These are symptoms that keep people from what most of us think of as the positive experiences in life, such as social relationships and the pleasure and ability to express emotions," said Dr Schooler.

"So while antipsychotic medications may help treat the major diagnostic hallmarks of schizophrenia and related illnesses, such as delusions, hallucinations, and disorganized thinking, what people are often left with is essentially an absence of experiences that they should be able to have, and restoring that is an important treatment goal in schizophrenia," she added.

Cariprazine, a dopamine D3/D2 receptor partial agonist that has been approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia in adults and for the treatment of mixed/manic episodes in patients with bipolar I disorder. It has previously been shown to improve both positive and negative symptoms.

However, earlier studies left unanswered the question as to whether the improvements resulted from the medication itself or came about because of improvements in other areas, such as improvements in positive symptoms.

In a phase 3b study published online in the Lancet, researchers affiliated with Gedeon Richter, Plc, a partner with the drug's manufacturer, Allergan, reported results of a multicenter, double-blind trial involving 460 patients at 66 study centers in Europe. In those studies, cariprazine was compared to risperidone monotherapy specifically for treatment of predominant negative symptoms in schizophrenia.

The study involved patients aged 18 to 65 years who had experienced the onset of schizophrenia at least 2 years prior to screening. The patients' conditions had been stable for at least the previous 6 months, and they had had predominantly negative symptoms for at least 6 months.

The participants were randomly allocated to groups of 230 patients each for treatment either with cariprazine at a dose of 3 mg, 4.5 mg (target dose), or 6 mg/day or risperidone at a dose of 3 mg, 4 mg (target dose), or 6 mg/day.

The results showed greater improvement in negative symptoms in the cariprazine group, with a least squares (LS) mean change in scores on Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) from baseline to 26 weeks of -8.90 points compared to -7.44 points in the risperidone group (P = .002; effect size = 0.31). The greater change from baseline that was seen in the cariprazine group began at week 14.

Practice Changing

Patients who received cariprazine also showed a greater response in the secondary efficacy parameter of LS mean change from baseline to the 26-week endpoint in the Personal and Social Performance scale (PSP) total score, with a change of 14.30 points vs 9.66 for risperidone (LS means difference, 4.63; effect size = 0.48). The greater change in the cariprazine group started at week 10 and extended until the endpoint.

More patients in the cariprazine group had a response to treatment, defined as a decrease in PANSS-FSNS scores of 20% or more, by 26 weeks than in the risperidone (odds ratio, 2.08; P = .002), with a number needed to treat of nine.

Greater improvements in the cariprazine group were also seen in parameters of the Clinical Global Impression–Improvement (CGI-I) and CGI-Severity scales.

There were no significant differences between the groups in treatment-emergent adverse events, including insomnia, akathisia, worsening of schizophrenia, headache, and anxiety, which were reported in 54% of cariprazine patients and 57% in the risperidone group.

"Given the lack of widely approved and clinically meaningful treatments, as well as the considerable unmet medical need in this vulnerable patient population, cariprazine has the potential to change clinical practice by providing a treatment option for patients with predominant negative symptoms of schizophrenia," the authors write.

"Treatment with cariprazine monotherapy not only improved predominant negative symptoms in patients with schizophrenia, but the effect was also clinically meaningful, as shown by improvement in patient functioning."

A separate post hoc analysis, described in a poster presented at the ASCP meeting, involved a pooled analysis of 317 patients among 1315 who met criteria for negative symptoms. In that analysis, greater improvement was seen with cariprazine at both doses compared to placebo (1.5 to 3 mg/day, P = .01; 4.5 to 6 mg/day, P = .0002). Improvements were also seen with risperidone (P = 01); there was no difference observed in an aripiprazole group.

Noting that the analysis adds interesting additional data, Dr Schooler underscored the fact that the Lancet study provides the most compelling evidence.

"I would call the poster interesting but not necessarily convincing, because it's a secondary analysis of patients with psychotic symptoms, and one could make the argument that as their positive symptoms improve, so do the negative symptoms.

"But the [Lancet] study, by targeting patients specifically with negative symptoms, is very convincing. While I would like to see an additional study, this is well-conducted study and does show an effect of the drug."

Mechanism Unclear

Dr Schooler could not comment on the mechanisms by which cariprazine treats negative symptoms, but he noted that there are numerous theories as to why no other antipsychotics treat the symptoms.

"One issue is that there is interaction with dopamine, and the effects of the drugs may cause some kind of dampening of emotional experiences. And if that is the case, not only would they not treat negative symptoms, but they may have some role in increasing their prevalence.

"While that is speculative, the data are abundantly clear that patients treated with the antipsychotics that we have continue to show negative symptoms, and questions remain regarding whether that is a mechanism of the illness itself or in some part a perverse effect of the drugs in treating the positive symptoms of psychosis."

William T. Carpenter Jr, MD, professor of psychiatry and pharmacology in the Department of Psychiatry at the Maryland Psychiatric Research Center, University of Maryland School of Medicine, in Baltimore, agreed that the effects of antipsychotics can be significant.

"If you or I were to take most of these antipsychotic drugs, our motivation for the day would probably be shot," he told Medscape Medical News.

He echoed the view regarding the strengths of the Lancet study, as well as the need for an approved treatment.

"Almost all studies have not used a methodology that would allow for a conclusion of efficacy, so the field badly needs a study like this that is attentive to the methodological requirements."

Importantly, the study avoids what the FDA calls pseudo-specificity, in which what is presented as the effect of a drug could be the result of something other than the drug, Dr Carpenter explained.

"If a patient, for instance, has paranoia and the paranoia is treated by the drug, then it makes sense that social withdrawal related to those fears would improve," he said.

"So it is important that in this study, these patients were stable and had negative symptoms that were long lasting."

The study still has its limitations and leaves open questions that future studies should address, Dr Carpenter noted.

"The drug isn't winning by any big margin, and it's hard to know how clinically meaningful the difference is. For me, the remaining question is whether the effects over risperidone are truly because of the drug or due to some other reason. But I am enthusiastic about this study because it is much better than anything else we have in the literature and suggests an advantage," he said.

The Lancet study and the meeting poster were sponsored by Gedeon Richter Plc. Dr Schooler has participated on advisory boards for Allergan and Roche regarding negative symptoms in psychosis. Dr Carpenter has disclosed no relevant financial relationships.

American Society of Clinical Psychopharmacology (ASCP) 2017 Annual Meeting.

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