Cariprazine (Vraylar) is a safe and effective adjunctive treatment for adults with major depressive disorder (MDD) who have an inadequate response to antidepressant monotherapy, new results from a phase 3 study show.
Already approved by the US Food and Drug Administration (FDA) 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 Medscape Medical News.
He noted that cariprazine, which is a partial agonist at D2, 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," Sachs said.
The findings were presented at the American Psychiatric Association (APA) 2022 Annual Meeting.
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, 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 (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants. They were recruited from 116 centers in the US and Europe.
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 Sachs.
In addition, at the start of the study, the participants had been depressed for almost eight 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," 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/d 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," 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 due to 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.
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," said Sachs.
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.
Another Potential Treatment Option
Commenting on the findings for Medscape Medical News, James Murrough, MD, PhD, associate professor of psychiatry and of neuroscience and director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai, New York City, said he welcomes research into additional treatments for MDD.
"Each medicine in a particular class has a unique pharmacology, so a larger number of medication options may help the clinician find a good match for a particular patient," said Murrough, who was not involved with the research.
He noted cariprazine is "somewhat unique" among the dopamine modulators in "preferring interactions with the D3 receptor, one of many types of dopamine receptors."
Although the study results showed cariprazine was effective in MDD, it "does not entirely break new ground" because previous research has already established the drug's efficacy as adjunctive therapy for patients with depression not responding to a standard antidepressant, said Murrough.
He also noted that the lower dose, but not the higher dose, of the drug was found to be significantly beneficial for patients compared with placebo.
"This is a good reminder that higher doses of a medication are not always better," Murrough said.
The study was funded by AbbVie. Sachs is a full-time employee of Signant Health, which conducted the training and quality control for this study. Murrough has reported no relevant financial relationships.
American Psychiatric Association (APA) 2022 Annual Meeting: Abstract P7-037. Presented May 24, 2022.
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Cite this: Antipsychotic Safe, Effective for Resistant Depression in Phase 3 Trial - Medscape - May 26, 2022.