Cariprazine Trumps Risperidone for Negative Schizophrenia Symptoms

Liam Davenport

July 09, 2020

The antipsychotic cariprazine (Reagila) is not only more effective than risperidone in treating patients with schizophrenia and persistent negative symptoms (PNS), it is also safe and effective for those who switch from prior, ineffective antipsychotic treatment, two new studies suggest.

Although functional outcome of schizophrenia is highly related to the presence and severity of PNS, "sufficient treatment of primary negative symptoms is still an unmet need," said co-investigator of the first analysis Barbara Sebe, MD, Gedeon Richter Plc, Budapest, Hungary.

"While cariprazine and risperidone were equally effective in controlling acute overall symptoms, only cariprazine improved predominant negative symptoms in acute patients. Furthermore, cariprazine is able to improve persistent primary negative symptoms. In fact, it was better than risperidone," she added.

All findings were presented at the European Psychiatric Association (EPA) 2020 Congress, which was virtual this year because of the COVID-19 pandemic.

Head-to-Head Comparison

In the first presentation, Sebe discussed a post-hoc analysis of the efficacy of cariprazine vs risperidone in treating acute and primary negative symptoms in schizophrenia.

She noted that previous studies on atypical antipsychotics, including risperidone, failed "to verify the effect" on PNS.

Because cariprazine has shown effectiveness in treating persistent PNS, the investigators conducted a two-part analysis of two phase 3 randomized controlled trials.

The first was a 6-week placebo- and risperidone-controlled trial of patients with acute symptoms of schizophrenia.

A full sample analysis was conducted of participants with baseline Positive and Negative Syndrome Scale (PANSS) total scores of between 80 and 120. Subgroup analysis of patients with PNS included 145 who were randomly assigned to receive cariprazine 4.5 mg per day, 67 to receive risperidone 4.0 mg per day, and 148 to receive placebo.

The second study was a 26-week risperidone-controlled trial in patients with PNS of at least 6 months' duration and who were stable in terms of their psychotic symptoms. In this, 35 patients were randomly assigned to receive cariprazine 4.5 mg per day, 16 to risperidone 4.0 mg per day, and 35 to placebo.

Results showed that both cariprazine 4.5 mg per day and risperidone 4.0 mg per day significantly reduced PANSS total scores from baseline vs placebo, with at least a square mean difference (LSMD) of -10.57 (P < .0001) and -13.17 (P < .0001), respectively.

There was no significant difference between the two treatment groups for PANSS total scores (P = .4071).

However, only cariprazine was associated with a significant reduction in PANSS factor score for negative symptoms (PANSS-FSNS) in patients with PNS, at an LSMD of -1.98 (P < .001) vs -0.813 for risperidone (P = .368).

Among patients with persistent PNS, 26 weeks of treatment with cariprazine was also associated with a greater reduction in PANSS-FSNS scores vs placebo, at an LSMD of -2.73 (P = .038) vs -1.56 for risperidone (P = .361).

There were no significant differences between the drugs in reduction of positive symptoms, depression, or movement scores.

"One can see that, while cariprazine and risperidone were equally effective in controlling acute overall symptoms, only cariprazine improved predominant negative symptoms in acute patients," Sebe said.

"Statistically More Effective"

Commenting on the findings for Medscape Medical News, Maurizio Fava, MD, executive director, Clinical Trials Network and Institute, Massachusetts General Hospital, Boston, noted "negative symptoms do not respond as robustly to antipsychotic treatment as positive symptoms."

In addition, negative symptoms "are known to have a major impact on the quality of life of patients and, for this reason, significant efforts have been made to identify molecules that would treat effectively both positive and negative symptoms," said Fava, who was not involved with the research.

He noted that cariprazine has previously been shown to be effective in preclinical models of anhedonia, and "more effective" than risperidone in patients with schizophrenia and PNS.

"The results presented at EPA 2020 support such findings, showing that cariprazine was relatively comparable to risperidone in its superiority to placebo with respect to positive symptoms of schizophrenia."

However, "only cariprazine, and not risperidone, was statistically significantly more effective than placebo in treating negative symptoms in patients with persistent, predominant negative symptoms," he added.

"First Real-Life Data"

In a second presentation, Elmars Rancans, MD, PhD, Department of Psychiatry and Addiction Disorders, Riga Stradins University, Riga, Latvia, discussed efficacy and safety of cariprazine in patients with schizophrenia who were previously treated with an antipsychotic.

The open-label, 16-week, observational study included adult participants from outpatient clinics across Latvia. The patients had negative symptoms based on clinical judgment and could be prescribed one of four cariprazine doses.

The patients had all received noneffective antipsychotic treatment, experienced adverse effects, and/or wished to switch drugs. They were also required to be "at least mildly ill" on the Clinical Global Impression-Severity scale (CGI-S) and to have not received cariprazine in the previous 30 days.

To measure cariprazine's efficacy, the researchers developed the Short Assessment of Negative Domains (SAND), a seven-point rating scale that assesses two positive symptom items (delusions and hallucinations) and five negative symptoms (anhedonia, affective flattening, avolition/apathy, alogia, and emotional and social withdrawal).

Similar to the Brief Negative Symptom Scale and the CGI-Schizophrenia scale, each item was rated from 0 to 6 and ranged from "not observed" to "extreme."

A total of 116 patients were included in the study, of whom 96 completed the trial.

SAND total scores significantly improved from baseline as early as week 2, with an LSMD by week 16 of -7.3 (P < .001). There were also significant improvements in negative symptoms, at an LSMD of -6.3 by week 16 (P < .001), and in positive symptoms, at an LSMD of -0.9 (P < .001).

Improvement in negative symptoms over baseline became significant by week 2, whereas improvement in positive symptoms reached significance at week 6.

CGI-Improvement scores also improved significantly from week 2 onward (P < .001), whereas CGI-S scores significantly decreased during the study period (P < .001).

Of the participants, 44% had preexisting adverse drug reactions when they entered the study, with akathisia (23%), parkinsonism (16%), and hyperprolactinemia (8%) the most common reactions.

Newly emergent adverse drug reactions were experienced by 41% of patients, with the most common being akathisia (13%), anxiety (10%), and parkinsonism (6%). The majority of these reactions were mild and decreased over time.

"To our knowledge, it's the first real-life data presented" on the efficacy of cariprazine, Rancans said.

He noted that, aside from the positive results, the investigators have shown that such a study is feasible and that "you can switch patients to cariprazine from different previous antipsychotic medication regimens."

The studies were funded by Gideon Richter. Sebe's study was also funded by Allergan. Sebe is an employee of Gedeon Richter, Plc. Fava reports he has conducted research on cariprazine in collaboration with Allergan. Rancans has disclosed no relevant financial relationships.

European Psychiatric Association (EPA) 2020 Congress. Abstracts EPP1128, EPV1351, and O0083. All presented July 6, 2020.

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