Deborah Brauser

May 23, 2012

May 23, 2012 (Philadelphia, Pennsylvania) — The antipsychotic cariprazine (Forest Laboratories Inc, Gedeon Richter Plc) is effective for treating mania in bipolar disorder (BD), new research suggests.

In results from a large phase 3 trial presented here at the American Psychiatric Association's (APA's) 2012 Annual Meeting, adult patients with acute mania associated with BD who received cariprazine showed significantly greater mania improvement scores and less symptom severity after 3 weeks of treatment than those receiving placebo.

Only 10% of the participants receiving cariprazine (vs 7% of those receiving placebo) stopped treatment because of adverse events (AEs). However, the group receiving the study drug also reported significantly more extrapyramidal symptom-related AEs than the placebo group, including akathisia and tremor.

Still, the investigators, led by Anju Starace, from Forest Research Institute in Jersey City, New Jersey, stated that the results show that cariprazine "was safe and generally well tolerated in this group of patients."

Different Mechanism

Oral cariprazine, which is also known as RGH-188, is a "D3-preferring dopamine D3/D2 receptor partial agonist," report the researchers.

"Higher affinity for and greater receptor antagonism at D3 versus D2 receptors may be associated with antipsychotic efficacy...and beneficial effects on mood," they add.

The experimental drug also has a "low potency at other receptor sites such as 5-HT2c, histamine H1, muscarinic, and adrenergic receptor sites, which have been associated with adverse events."

As reported earlier this year by Medscape Medical News, results from 2 phase III trials showed that cariprazine was more effective than placebo in treating acute exacerbation of schizophrenia.

In a statement released at the time, the manufacturers reported that the drug is also being investigated as an adjunctive treatment for patients with major depressive disorder.

For the current 6-week study, investigators enrolled 312 patients between the ages of 18 and 65 years with BD who had a score of 20 or greater on the Young Mania Rating Scale (YMRS).

Patients were randomly assigned to receive for 3 weeks either 3- to 12-mg/day dosages of cariprazine (n = 158) or matching placebo (n = 154). This was followed by a 4- to 7-day in-hospital "washout screening," and then a 2-week safety follow-up period.

The primary efficacy measure was total change in score from baseline to end of week 3 on the YMRS. Secondary measures included Clinical Global Impressions-Severity (CGI-S) scores. AEs, clinical laboratory values, electrocardiograms, vital signs, and extrapyramidal symptoms were also assessed.

An Improved Aripiprazole?

Results showed that the cariprazine group had significantly better improvement scores on the YMRS than did the placebo group (mean deviation, -4.3; P < .001) and greater improvements on the CGI-S (P < .01).

Premature discontinuance rates were 32% for those receiving cariprazine and 31% for those receiving placebo. The rates of discontinuance due to AEs were 10% and 7%, respectively.

Treatment-related AEs were reported by 80% of the cariprazine group vs 63% of the placebo group. The most common AEs for the cariprazine group (defined as ≥10%, which occurred at twice the rate seen in the patients receiving placebo) were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting.

Extrapyramidal symptom-related AEs were reported by 46% of the patients receiving cariprazine and by 12% of those receiving placebo.

"Cariprazine seems like a new and possibly improved aripiprazole," Nassir Ghaemi, MD, MPH, professor of psychiatry at Tufts University School of Medicine and director of the Mood Disorders Program at Tufts Medical Center in Boston, Massachusetts, wrote in a Medscape Connect blog post during the APA meeting.

"Will this biological twist make a clinical difference? We'll see. For now, this drug was proven effective in double-blind placebo-controlled randomized trials in acute mania and schizophrenia," said Dr. Ghaemi, who was not involved with this study.

"Me Too" Drug

Stephen J. Ferrando, MD, professor of clinical psychiatry and public health and vice-chair of the Division of Psychosomatic Medicine at the New York-Presbyterian Hospital/Weill Cornell Medical Center in New York City, echoed some of Dr. Ghaemi's comments when talking with Medscape Medical News.

Dr. Stephen Ferrando

"This is a medication among a class of drugs that is supposed to have potential benefits and fewer side effects in patients with schizophrenia and bipolar disorders. It's a partial agonist at the D2 and D3 receptors, which is somewhat like aripiprazole or Aricept [donepezil], which is already in common use and approved for acute bipolar mania and for schizophrenia," he said.

Dr. Ferrando, who was not involved in this study, added that the new medication's agonist effects "supposedly confer...positive improvements in mood and cognition."

He noted that it also "has low affinity for a lot of the receptor subtypes that cause side effects like antihistaminic effects, which confers risks for things like weight gain and metabolic syndrome."

Because "we already have a drug out there that is similar," Dr. Ferrando said that it is especially important to assess how efficacious and safe this new option really is.

"This was a well-designed, multisite clinical trial where the patients were fairly ill. And you do see a drug-placebo difference, which is the good news," he said.

"The less than good news is that it appears that extrapyramidal symptom side effects are greater in the drug compared to the placebo arm. That's somewhat disappointing, although not unexpected because we know that a similar thing happens with aripiprazole. You get things like akathisia and some dystonias," said Dr. Ferrando.

"In terms of whether or not this is basically just a 'me too' drug or advances the field, these results don't really support the latter other than providing another alternative."

He added that a head-to-head study between cariprazine and aripiprazole "is needed but unlikely."

The study was funded by Forest Laboratories Inc and Gedeon Richter Plc. Starace is an employee of the Forest Research Institute. Dr. Ferrando has disclosed no relevant financial relationships.

The American Psychiatric Association's 2012 Annual Meeting. Abstract Poster #NR9-42. Presented May 8, 2012.

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