, new results from a phase 3 study show.
Already approved by the U.S. Food and Drug Administration to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder, cariprazine is under investigation as an add-on therapy for MDD.
“Even patients who appear to be nonresponsive to standard antidepressant drugs have a very good chance of responding” to cariprazine, lead study author Gary Sachs, MD, associate clinical professor of psychiatry at Massachusetts General Hospital, Boston, told this news organization.
Dr. Gary Sachs
He noted that cariprazine, which is a partial agonist at D2 and D3, as well as 5-HT1A, “is an entirely different class” of drugs.
“It’s worth understanding how to use drugs like cariprazine and expanding our nomenclature; instead of referring to these drugs as atypical antipsychotics, perhaps referring to them as atypical antidepressants makes more sense,” Dr. Sachs said.
The findings were presented at the annual meeting of the American Psychiatric Association.
More options critical
MDD is among the most common psychiatric disorders in the United States. In 2020, an estimated 21 million adults had at least one major depressive episode.
Previous research has shown almost half of patients with MDD do not experience satisfactory results from their current treatment regimen. Therefore, research on more options for patients is critical, Dr. Sachs said.
Results from a previously published placebo-controlled study showed adjunctive treatment with cariprazine at 2-mg to 4.5-mg per day doses was more effective than placebo in improving depressive symptoms in adults with MDD.
The new analysis included patients with MDD and an inadequate response to antidepressant therapy, including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants. They were recruited from 116 centers in the United States and Europe.
Dr. Sachs noted that a nonresponse to an adequate dose of an antidepressant typically means having less than a 50% improvement over 6 weeks or more.
Researchers randomly assigned the patients to oral cariprazine 1.5 mg/day, cariprazine 3 mg/day, or placebo. All continued to take their antidepressant monotherapy.
The analysis included 757 mostly White participants (mean age, 44.8 years; 73.4% women). All had experienced depression for a “huge” part of their life (average, about 14 years), “not to mention their adult life,” said Dr. Sachs.
In addition, at the start of the study, the participants had been depressed for almost 8 months on average.
The primary endpoint was change at week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The mean baseline MADRS total score was 32.5.
Less is sometimes more
Results showed a significantly greater mean reduction in MADRS total score for cariprazine 1.5 mg/day vs. placebo at week 6 (P = .005). Significant differences from placebo were observed as early as week 2 and were maintained at week 4, as well as week 6.
“I can say with great confidence that the 1.5-mg dose met all the standards for efficacy,” Dr. Sachs said.
However, this was not the case for the 3-mg/day dose. Although there was a numerically greater reduction in MADRS total score for this dosage of the drug vs. placebo at week 6, the difference was not statistically significant (P = .07).
At week 6, more patients taking the active drug at 1.5 mg/day than placebo responded to treatment, defined as 50% or greater reduction in MADRS total score (44% vs. 34.9%, respectively; P < .05).
Researchers also assessed scores on the Clinical Global Impressions, finding significantly greater score improvement for both the 1.5-mg/day (P = .0026) and 3-mg/day (P =.0076) groups vs. the placebo group.
Improvement at week 6 in mean total score on the Hamilton Depression Rating Scale (HAM-17) reached nominal significance for cariprazine 1.5 mg/day vs. placebo – but not for 3 mg/day.
The results of this “high-quality” double-blind, randomized, controlled, parallel group study provide “what I regard as proven efficacy,” Dr. Sachs said.
He added that the investigational drug was also relatively safe. “The vast majority of patients tolerated it quite well,” he stressed. In addition, the drop-out rate because of adverse events was “quite low overall.”
The only adverse events (AEs) that occurred with the active treatment at a frequency of 5% or more and double that of placebo were akathisia and nausea. Changes in weight were relatively small, at less than 1 kg, in all treatment groups.
There was one serious AE in each active drug group, one of which was a kidney infection. There were two serious AEs reported in the placebo group, including one patient with multiple sclerosis. There were no deaths.
Dr. Sachs noted an advantage of cariprazine is its long half-life, which makes it more user-friendly because “it forgives you if you miss a dose or two.”
Drug manufacturer AbbVie’s supplemental New Drug Application for cariprazine is currently under review by the FDA for expanded use as adjunctive treatment of MDD. A decision by the agency is expected by the end of this year.