Frequently Asked Questions

No. In this phase 3 trial, adjunctive cariprazine did not separate significantly from placebo on the primary endpoint at week 6. Least squares mean change in MADRS total score was -13.8 with cariprazine 1.5 mg/day, -14.8 with cariprazine 3 mg/day, and -13.4 with placebo, and the least squares mean differences versus placebo were not statistically significant for either dose.

There were early numerical trends favoring cariprazine, but they were not statistically significant because they were not adjusted for multiple comparisons. The study reported that change from baseline in MADRS total score favored cariprazine 3 mg/day versus placebo at weeks 1, 2, and 4 and favored cariprazine 1.5 mg/day at week 2; at weeks 2 and 4, the difference for cariprazine 3 mg/day versus placebo was about 2 MADRS points.

Cariprazine did not show a statistically significant advantage over placebo on the key secondary endpoint of CGI-S score change at week 6. The strongest signal was with cariprazine 3 mg/day, which had a least squares mean difference versus placebo of -0.2 with a 95% confidence interval of -0.43 to 0.01 and a nominal P value of .0573, but this was not significant and was not adjusted for multiplicity.

MADRS response rates were numerically higher with cariprazine, but the differences were not significant in this trial. The discussion reports that MADRS response was achieved by 46% of patients receiving cariprazine 1.5 mg/day, 48% receiving cariprazine 3 mg/day, and 41% receiving placebo; no significant differences were seen in rates of MADRS response or remission at week 6.

Akathisia and insomnia were the most common treatment-emergent adverse events that occurred in at least 5% of patients and at at least twice the placebo rate. Most treatment-emergent adverse events were mild or moderate, and fewer than 1% of patients in any group had a serious treatment-emergent adverse event; none of those serious events were considered related to treatment.

Scale-derived treatment-emergent akathisia was more common with cariprazine than with placebo. It was reported in 13 of 249 placebo-treated patients (5.2%), 27 of 250 patients receiving cariprazine 1.5 mg/day (10.8%), and 30 of 251 patients receiving cariprazine 3 mg/day (12.0%).

Yes, akathisia was the only treatment-emergent adverse event that led to discontinuation in more than 1 patient in any group. Discontinuation because of akathisia occurred in 2 patients (0.8%) on cariprazine 1.5 mg/day, 6 patients (2.4%) on cariprazine 3 mg/day, and 2 patients (0.8%) on placebo.

Short-term metabolic and cardiac changes were limited over 6 weeks. Mean weight change was 0.20 kg with placebo, 0.68 kg with cariprazine 1.5 mg/day, and 0.66 kg with cariprazine 3 mg/day; weight gain of at least 7% occurred in 0.8%, 0.4%, and 2.0% of patients, respectively. No patient in any group had a QTcF increase greater than 60 msec from baseline or a QTcF interval greater than 500 msec, and no patients met Hy's Law criteria.

The trial did not show an increased risk of suicidality during double-blind treatment compared with placebo. C-SSRS-rated suicidal ideation occurred in 5.2% of patients on cariprazine 1.5 mg/day, 7.6% on cariprazine 3 mg/day, and 6.4% on placebo; most events were in the least serious category, and no suicidal behavior or completed suicide occurred during double-blind treatment. Treatment-emergent mania was reported in 1 placebo patient and in no cariprazine-treated patients.

The study enrolled adults aged 18 to 65 years with DSM-5 major depressive disorder who were in a current major depressive episode lasting at least 8 weeks and less than 24 months and who had an inadequate response, defined as less than 50% improvement, to 1 to 3 antidepressants of adequate dose and duration during the current episode. Patients also had to have an HDRS17 total score of at least 22 and an Item 1 score of at least 2 at baseline.

This was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial conducted at 107 sites. After screening, patients were randomized 1:1:1 to cariprazine 1.5 mg/day plus ongoing antidepressant therapy, cariprazine 3 mg/day plus ongoing antidepressant therapy, or placebo plus ongoing antidepressant therapy for 6 weeks, followed by a 4-week safety follow-up.

The authors identified several limitations: the study duration was short, there was no active comparator, and the strict inclusion and exclusion criteria may limit generalizability to other patients with major depressive disorder. They also noted that ongoing antidepressant treatment could have contributed to symptom reduction during the trial and that high placebo response, possibly including effects related to study participation during the COVID-19 pandemic, may have reduced the ability to detect a treatment effect.